1. Field of the Invention
This invention relates to a group of compounds with anti-mycobacterial activities that have a common hydroxamic acid structural feature and to methods for using same. This invention also relates to compositions including an hydroxamate and an hydroxylamine which possess anti-mycobacterial activity and to methods for making and using same.
More particularly, the present invention relates to compositions capable of inhibiting mycobacterium tuberculosis in standard mycobacterial growth assays, where the compositions include a therapeutically effective amount of an hydroxamate or an therapeutically effective amount of an hydroxamate and an hydroxylamine and to methods for using same.
2. Description of the Related Art
With the rapid evolution of bacterial resistance to antibiotic therapy there is a constant need for new generations of drugs, and to attain this there is a need for new targets on which to focus the development of antibiotics. As part of a computer based drug design project we are addressing the development of novel inhibitors of the alanine racemase from various pathogenic organisms. This enzyme is required for the biosynthesis of the cell wall of all bacteria including mycobacteria. Because humans do not contain an alanine racemase gene, and do not have a use for this product, d-alanine, it is a logical target for the development of specific antibacterial agents.
You are in receipt of a series of publications that relate to the medical use of hydroxamate compounds. They describe the study of similar agents in malaria, cancer, toxin deactivation, and as t-RNA synthetase inhibitors. Some of these publications specifically refer to the use of hydroxamic acid and related compounds against tuberculosis. These references include, but are not limited to the following papers: (1) Gale, G. R. and. Hynes, J. B., “Further studies of the antimycobacterial agents glycyl laydroxamic acid and ˜-alanyl hydroxamie acid”(1966) Canadian J. Micro. (12), 73-81. (2) Gale, G. R. and Hawldns, J. E., “Antimycobacterial properties of glycyl hydroxamic acid and ˜-alanyl hydroxamic acid”, Am. Rev. Respiratory Dis. (92), 642-646.
Notably some of these compounds were shown in these reports to possess activity in animal models of tuberculosis and to lack significant toxicity. Following these types of studies it would be usual and customary to conduct confirmatory animal and toxicity studies. If these studies were promising, then human trials might be initiated. We have not as yet located the results of any further testing or trials for the compounds reported above.
Alanine racemase is necessary for cell wall biosynthesis in bacteria. Because humans do not have the alanine racemase gene and do not need the product it produces, it is a logical target for the development of specific antibacterial agents. Inhibitors of alanine racemase currently used (cycloserine) have neurological and other side effects because they are not specific to alanine racemase and inhibit the activity of other PLP-dependent enzymes. Cycloserine is currently used as a second-line drug against mycobacterium. Unfortunately, the use of cycloserine is limited because certain strains of mycobacterium have developed a resistance to it, and it has serious adverse effects including CNS toxicity and drug-induced psychosis. The need for new antibacterial agents that selectively inhibit only alanine racemase without causing side effects is obvious.